Circulation. 2008;118:2115-2116
doi: 10.1161/CIRCULATIONAHA.108.191127
(Circulation. 2008;118:2115-2116.)
© 2008 American Heart Association, Inc.
Clinical Summaries
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Downloadable Algorithm to Reduce Inappropriate Shocks Caused by Fractures of Implantable Cardioverter-Defibrillator Leads
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Fractures of pace-sense electrodes in implantable cardioverter-defibrillator
patients are a common cause of inappropriate shocks. These fractures
result in high pacing impedance and oversensing of rapid, nonphysiological
potentials. Despite automated, daily measurements of impedance
to provide advance warning, their most common presentation is
inappropriate shocks. We developed and tested an algorithm to
enhance early identification of lead fractures and to reduce
inappropriate shocks. This lead-integrity algorithm, which can
be downloaded into presently implanted implantable cardioverter-defibrillators,
alerts the patient and/or physician when triggered by either
oversensing or abnormal impedance. Because oversensing associated
with lead fracture typically is transient, we hypothesized that
increasing the number of intervals to detect ventricular fibrillation
reduces inappropriate shocks. Thus, the lead-integrity algorithm
also increases the number of intervals to detect ventricular
fibrillation when triggered. In a simulated retrospective analysis,
the lead-integrity algorithm improved advance warning of lead
fractures compared with present impedance monitoring. Its clinical
value depends on rapid response to alerts by the patient and
physician. This lead-integrity algorithm is the first downloadable
RAMware developed to enhance the performance of nominally functioning
implantable cardioverter-defibrillators and is the first implantable
cardioverter-defibrillator monitoring feature that triggers
real-time changes in ventricular fibrillation detection parameters
to reduce inappropriate shocks. See p
2122.
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A Randomized Trial of On-Pump Beating Heart and Conventional Cardioplegic Arrest in Coronary Artery Bypass Surgery Patients With Impaired Left Ventricular Function Using Cardiac Magnetic Resonance Imaging and Biochemical Markers
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Although the financial burden of heart failure is growing in
the United States, surgical research in this area is limited
by difficult patient demographics. Coronary artery bypass grafting
(CABG) affects both mortality and morbidity in heart failure
patients; however, the benefits are balanced heavily by high
operative risks. Beating heart CABG has benefits in terms of
postoperative morbidity; however, the application of this technique
in patients with impaired ventricular function remains untested.
In a small randomized trial of patients with severe coronary
artery disease and impaired ventricular function, a novel hybrid
approach of on-pump beating heart surgery (ONBEAT) was compared
with conventional cardioplegic arrest (ONSTOP). Left ventricular
function and injury were assessed with cardiac magnetic resonance
imaging before and 7 days after surgery with additional serial
assessment of cardiac biochemical markers over the first 120
hours. Counterintuitively, the study clearly demonstrates a
higher incidence of myocardial injury associated with the novel
ONBEAT approach. We conclude that physiological coronary perfusion
in patients with severe proximal coronary disease may not be
sufficient to perfuse distal coronary beds, and in the absence
of formal myocardial protection with cardioplegia, it renders
these territories ischemic. Although this study is small, it
has important implications for the application of beating heart
techniques in patients with inadequate cardiac output and severe
coronary artery disease. See p
2130.
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Antiplatelet Therapy Use After Discharge Among Acute Myocardial Infarction Patients With In-Hospital Bleeding
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Although bleeding in the setting of an acute myocardial infarction
is known to be associated with worse long-term outcomes, the
mechanism is unclear. Our study suggests an explanation: Proven
secondary prevention therapies, such as antiplatelet agents,
are withheld long beyond the resolution of the bleeding event.
Postdischarge cardiology follow-up was associated with greater
antiplatelet therapy use than either primary care or no clinical
follow-up. Thus, early reassessment of antiplatelet eligibility
may represent an opportunity to reduce the long-term risks associated
with bleeding, and future larger studies examining the impact
of early antiplatelet medication resumption on ischemic and
bleeding outcomes are warranted. See p
2139.
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Collectrin Is Involved in the Development of Salt-Sensitive Hypertension by Facilitating the Membrane Trafficking of Apical Membrane Proteins via Interaction With Soluble N-Ethylmaleiamide–Sensitive Factor Attachment Protein Receptor Complex
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Salt-sensitive hypertension is a common clinical problem, particularly
in certain subsets of hypertensive patients, including blacks,
the elderly, and patients with chronic kidney disease. Recent
long-term follow-up data suggest that even a short period of
dietary salt restriction significantly improves cardiovascular
risk. Accordingly, identifying mechanisms of salt sensitivity
is clinically important. The renin-angiotensin-aldosterone system
plays a central role in salt handling in the kidney, and aldosterone
upregulates Sgk1 and recruits
-epithelial Na
+ channel on the
apical membrane, which results in sodium retention. However,
aldosterone levels are significantly reduced under a high-salt
diet, and the mechanism of salt-sensitive hypertension is not
well understood. The present studies link collectrin, a transmembrane
protein localized to the apical membrane of collecting duct
cells, to sodium retention in rats exposed chronically to high
dietary salt. Collectrin binds to the soluble
N-ethylmaleiamide–sensitive
factor attachment protein receptor (SNARE) complex, and upregulation
of collectrin by a high-salt diet independent of aldosterone
functionally links to the facilitation of vesicle fusion and
trafficking of apical membrane proteins such as
-epithelial
Na
+ channel. In clinical settings, blockade of the renin-angiotensin-aldosterone
system by a renin inhibitor, angiotensin-converting enzyme inhibitor,
angiotensin receptor antagonist, and selective aldosterone blockers
is a major therapeutic option to prevent cardiovascular events
and the progression of chronic kidney disease. Upregulation
of collectrin in collecting duct cells by a high-salt diet may
blunt the efficacy of renin-angiotensin system inhibitors in
salt-sensitive hypertension. Salt restriction is further warranted
in the clinic, and collectrin may be the new therapeutic target
in hypertension. See p
2146.
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Transcriptional Regulation of Bim by FOXO3a and Akt Mediates Scleroderma Serum–Induced Apoptosis in Endothelial Progenitor Cells
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The origin of systemic sclerosis is still not completely understood
but appears to be autoimmune. Immune activation targets mature
endothelial cells, resulting in vascular integrity breakdown
and ensuing fibrosis. Endothelial progenitor cells (EPCs) are
bone marrow–derived nonleukocyte cells that participate
in vascular repair and homeostasis. It has been shown that injury
of endothelial cells not only induces a cascade of proinflammatory
events, contributing to vascular lesion formation, but also
stimulates the mobilization of EPCs from the bone marrow, mediating
vascular repair. Hence, the availability of circulating EPCs
plays a critical role in maintaining the integrity and functional
activity of the endothelial monolayer and in vasculogenesis.
Several lines of evidence indicate that increased demand for
vascular repair in the context of repeated injury could exhaust
the supply of EPCs in the bone marrow, interrupting the balance
between vascular repair and injury. In this report, we provide
evidence showing, for the first time, that the factors in the
peripheral blood of systemic sclerosis patients that cause endothelial
cell injury also may damage EPCs. Moreover, probably owing to
the lack of protective mechanisms in these immature cells, EPCs
are more sensitive to the toxic factors than endothelial cells,
implicating excessive EPC destruction in the pathogenesis of
systemic sclerosis. Importantly, we have identified an Akt-FOXO3a-Bim
pathway to mediate EPC apoptosis. Although much work needs to
be done to determine the exact factors in the systemic sclerosis
serum causing EPC apoptosis, targeting the Akt-FOXO3a-Bim pathway
may be considered a venue for future therapies. See p
2156.
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Increased Vascular Senescence and Impaired Endothelial Progenitor Cell Function Mediated by Mutation of Circadian Gene Per2
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Alteration of the circadian rhythm is associated with increased
incidence of pathological diseases such as sleep disorders,
cardiovascular diseases, metabolic syndromes, and cancers. However,
the mechanism by which alteration of the circadian rhythm leads
to impaired vascular function is not known. In this study, we
showed that mutation of the circadian gene,
Per2, in mice leads
to increased vascular senescence or aging through excessive
activation of protein kinase Akt. This was associated with decreased
endothelial cell proliferation and impaired vascular network
formation. Indeed, compared with normal or wild-type mice,
Per2 mutant (Per2
m/m) mice exhibit defective angiogenic response
to distal limb ischemia as a result of endothelial dysfunction
and impaired mobilization of endothelial progenitor cells. When
Per2
m/m mice were injected with bone marrow–derived endothelial
progenitor cells or mated with haploinsufficient Akt1
+/– mutant mice to reduce excessive Akt activation, the impaired
angiogenic response, endothelial cell proliferation, and vascular
network formation were completely rescued or restored. These
findings suggest that polymorphisms or alteration of circadian
genes may be linked to cardiovascular disease through increased
vascular senescence, endothelial dysfunction, and impaired bone
marrow stem cell function. Thus, restoration of circadian gene
function and prevention of excessive Akt activation may lead
to mitigation of age-related vascular diseases. See p
2166.
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Inhibition of Protein Kinase Cβ Prevents Foam Cell Formation by Reducing Scavenger Receptor A Expression in Human Macrophages
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Low-density lipoprotein (LDL) uptake by monocyte-derived macrophages
is a hallmark and key event of early atherogenesis. On exposure
to modified lipoproteins such as oxidized LDL and acetylated
LDL, these macrophages become foam cells. Increasing evidence
supports that activation of PKCβ is involved in many mechanisms
promoting atherosclerosis. In this study, we demonstrate that
inhibition of protein kinase Cβ (PKCβ) prevents uptake
of modified LDL by reducing human monocyte-derived macrophage
scavenger receptor A expression. Several studies have strongly
implicated activation of PKCβ in the pathogenesis of the
vascular complications of diabetes. The synthesis of isoform-specific
inhibitors for PKCβ has provided not only important insights
into diabetic cardiovascular disease but also effective drugs
against its microvascular complications. Interestingly enough,
our data unmask an antiatherosclerotic effect of PKCβ inhibitors
even in the nondiabetic condition of hypercholesterolemia. Specific
siRNA-mediated knockdown of PKCβ further supports our conclusion.
Indeed, on silencing of PKCβ, LDL uptake was blunted, scavenger
receptor A expression was reduced, and hence foam cell formation
was prevented. Of particular interest is the fact that in our
study the PKCβ inhibitor LY379196, as a drug targeting
macrophages, prevents only foam cell formation without affecting
macrophage host defense activity. Although PKCβ inhibitors
are currently being tested in clinical trials with microvascular
end points, the present findings suggest a role for PKCβ
in atherogenesis even in the nondiabetic condition and anticipate
the application of PKCβ inhibitors as putative antiatherosclerotic
drugs. See p
2174.
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Exercise-Induced Pulmonary Arterial Hypertension
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We provide the first large invasive characterization of symptomatic
patients with exercise-induced pulmonary arterial hypertension
(PAH). In contrast to previous studies that utilized stress
echocardiography, our use of in-dwelling pulmonary arterial
catheters during maximum incremental cardiopulmonary exercise
testing allows the appropriate exclusion of patients whose exertional
pulmonary hypertension is due to either elevated left-sided
filling pressures or increased cardiac output (and normal pulmonary
vascular resistance). We further demonstrate that the patient
with exercise-induced PAH has physiological characteristics
that are intermediate between those with normal values and those
with resting PAH. We conclude that exercise-induced pulmonary
arterial hypertension is a mild but clinically relevant form
of PAH. Given the progressive nature of PAH, our findings may
have important implications in its early recognition and treatment.
See p
2183.
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